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AR082888A1 - PIRIDINE COMPOUNDS FOR THE INHIBITION OF NAMPT - Google Patents

PIRIDINE COMPOUNDS FOR THE INHIBITION OF NAMPT

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Publication number
AR082888A1
AR082888A1 ARP110103221A ARP110103221A AR082888A1 AR 082888 A1 AR082888 A1 AR 082888A1 AR P110103221 A ARP110103221 A AR P110103221A AR P110103221 A ARP110103221 A AR P110103221A AR 082888 A1 AR082888 A1 AR 082888A1
Authority
AR
Argentina
Prior art keywords
aryl
alkyl
propenamide
pyridinyl
sulfonyl
Prior art date
Application number
ARP110103221A
Other languages
Spanish (es)
Original Assignee
Forma Therapeutics Inc
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Forma Therapeutics Inc filed Critical Forma Therapeutics Inc
Publication of AR082888A1 publication Critical patent/AR082888A1/en

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    • C07D213/00Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/24Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with substituted hydrocarbon radicals attached to ring carbon atoms
    • C07D213/36Radicals substituted by singly-bound nitrogen atoms
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    • C07D213/02Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/24Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with substituted hydrocarbon radicals attached to ring carbon atoms
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Abstract

La presente se relaciona con compuestos y composiciones para inhibir NAMPT (nicotinamida fosforribosiltransferasa), sus síntesis, aplicaciones y antídotos. Uso antitumoral.Reivindicación 1: Compuestos de fórmula (1) donde: Ar es arilo o heteroarilo, cada uno de dichos arilo y heteroarilo está sin sustituir u opcional e independientemente sustituido con 1, 2, 3 ó 4 sustituyentes los cuales pueden ser iguales o diferentes y se seleccionan independientemente del grupo que consiste en deuterio, halo, ciano, amino, aminoalquil-, (amino)alcoxi-, -CONH2, -C(O)NH(alquilo), -C(O)N(alquilo)2, -C(O)NH(arilo), -C(O)N(arilo)2, -CHzF3-z, -OCHzF3-z, -alquilo, -alquenilo, -alquinilo, -alcoxi, (alcoxialquil)amino-, -N(R3)-C(O)-alquilo, -N(R3)-C(O)-arilo, cicloalquilo, heterocicloalquilo, arilo y heteroarilo; R1 es -NRaRb, donde Ra es H, alquilo o -S(O)2alquilo y Rb es alquilo, hidroxialquilo, -S(O)2alquilo, -(CH2)q-cicloalquilo, -(CH2)q-heterocicloalquilo, arilo, arilalquil-, -(CH2)q-heteroarilo; cicloalquilo; heterocicloalquilo; arilo; heteroarilo; cada uno de dicho cicloalquilo, heterocicloalquilo, arilo, o heteroarilo está sin sustituir o sustituido con 1, 2, 3, 4 ó 5 sustituyentes los cuales pueden ser iguales o diferentes y se seleccionan independientemente del grupo que consiste en deuterio, halo, ciano, alquilo, hidroxilo, hidroxialquilo, hidroxialcoxi, cianoalquilo, haloalquilo, alquenilo, alquinilo, alcoxi, alquilalcoxi, haloalcoxi, arilalquenil-, ariloxi, benciloxi, oxo, -(CH2)q-NRcRd, -(CH2)q-CONRcRd, -S(O)2-alquilo, -S(O)2-arilo, -S(O)2NH2, -S(O)2NH-alquilo, -S(O)2N(alquilo)2, -S(O)2-heterocicloalquilo, -S(O)2-CF3, -C(O)alquilo, -C(O)arilo, -C(O)alquilenilarilo, -C(O)O-alquilo, -NH-C(O)alquilo, -NH-C(O)arilo, metilendioxi, -(CH2)q-cicloalquilo, cicloalquilalcoxi-, arilo, arilalquil-, -(CH2)q-heteroarilo, y -(CH2)q-heterocicloalquilo, donde cada uno de dicho cicloalquilo, heterocicloalquilo, arilo o heteroarilo puede ser sustituido por uno o más halo, nitro, haloalquilo, haloalcoxi, oxo, ciano, alquilo, haloalquilo, o alcoxi; y Rc y Rd se seleccionan independientemente del grupo que consiste en H, alquilo, hidroxialquilo, alcoxi, arilo, alcoxialquilo, -S(O)2alquilo y cicloalquilo o Rc y Rd pueden formar un grupo heterocicloalquilo de 5 ó 6 miembros junto con el átomo de nitrógeno al cual están unidos, donde dicho grupo heterocicloalquilo puede contener uno o más heteroátomos adicionales seleccionados entre N, S u O; z es 0, 1 ó 2; q es 0, 1, 2, 3 ó 4; y sus sales farmacéuticamente aceptables, con la condición de que el compuesto de fórmula (1) no sea N-[3-(ciclopentilsulfonil)fenil]-3-(3-piridinil)-2-propenamida; N-[4-etoxi-3-(4-morfolinilsulfonil)fenil]-3-(3-piridinil)-2-propenamida; N-[2-(1-metiletoxi)-5-(4-morfolinilsulfonil)fenil]-3-(3-piridinil)-2-propenamida; N-[2-etoxi-5-(4-morfolinilsulfonil)fenil]-3-(3-piridinil)-2-propenamida; N-[5-[(hexahidro-1Hazepin-1-il)sulfonil]-2-(2,2,2-trifluoretoxi)fenil]-3-(3-piridinil)-2-propenamida; N-[5-[(dietilamino)sulfonil]-2-(4-morfolinil)fenil]-3-(3-piridinil)-2-propenamida; N-[3-[[(3-clorofenil)amino]sulfonil]-4-metilfenil]-3-(3-piridinil)-2-propenamida; N-[3-[[(4-clorofenil)amino]sulfonil]-4-metilfenil]-3-(3-piridinil)-2-propenamida; 3-(3-piridinil)-N-[4-[[(tetrahidro-1,1-dioxido-3-tienil)amino]sulfonil]fenil]-2-propenamida; 3-(3-piridinil)-N-[3-[[[3-(trifluormetil)fenil]amino]sulfonil]fenil]-2-propenamida; y@@@3-(3-piridinil)-N-[1,4,5,6-tetrahidro-5-[(4-metilfenil)sulfonil]pirrolo[3,4-c]pirazol-3-il]-2-propenamida.This is related to compounds and compositions for inhibiting NAMPT (nicotinamide phosphoribosyltransferase), their synthesis, applications and antidotes. Antitumor use. Claim 1: Compounds of formula (1) wherein: Ar is aryl or heteroaryl, each of said aryl and heteroaryl is unsubstituted or optional and independently substituted with 1, 2, 3 or 4 substituents which may be the same or different and are independently selected from the group consisting of deuterium, halo, cyano, amino, aminoalkyl-, (amino) alkoxy-, -CONH2, -C (O) NH (alkyl), -C (O) N (alkyl) 2 , -C (O) NH (aryl), -C (O) N (aryl) 2, -CHzF3-z, -OCHzF3-z, -alkyl, -alkenyl, -alkynyl, -alkoxy, (alkoxyalkyl) amino-, -N (R3) -C (O) -alkyl, -N (R3) -C (O) -aryl, cycloalkyl, heterocycloalkyl, aryl and heteroaryl; R1 is -NRaRb, where Ra is H, alkyl or -S (O) 2alkyl and Rb is alkyl, hydroxyalkyl, -S (O) 2alkyl, - (CH2) q-cycloalkyl, - (CH2) q-heterocycloalkyl, aryl, arylalkyl-, - (CH2) q-heteroaryl; cycloalkyl; heterocycloalkyl; aryl; heteroaryl; each of said cycloalkyl, heterocycloalkyl, aryl, or heteroaryl is unsubstituted or substituted with 1, 2, 3, 4 or 5 substituents which may be the same or different and are independently selected from the group consisting of deuterium, halo, cyano, alkyl, hydroxyl, hydroxyalkyl, hydroxyalkoxy, cyanoalkyl, haloalkyl, alkenyl, alkynyl, alkoxy, alkylalkoxy, haloalkoxy, arylalkenyl-, aryloxy, benzyloxy, oxo, - (CH2) q-NRcRd, - (CH2) q-CONRcRd (CON O) 2-alkyl, -S (O) 2-aryl, -S (O) 2NH2, -S (O) 2NH-alkyl, -S (O) 2N (alkyl) 2, -S (O) 2-heterocycloalkyl , -S (O) 2-CF3, -C (O) alkyl, -C (O) aryl, -C (O) alkylenylaryl, -C (O) O-alkyl, -NH-C (O) alkyl, - NH-C (O) aryl, methylenedioxy, - (CH2) q-cycloalkyl, cycloalkylalkoxy-, aryl, arylalkyl-, - (CH2) q-heteroaryl, and - (CH2) q-heterocycloalkyl, where each of said cycloalkyl, heterocycloalkyl, aryl or heteroaryl can be substituted by one or more halo, nitro, haloalkyl, haloalkoxy, oxo, cyano, alkyl, haloalkyl, or alkoxy; and Rc and Rd are independently selected from the group consisting of H, alkyl, hydroxyalkyl, alkoxy, aryl, alkoxyalkyl, -S (O) 2alkyl and cycloalkyl or Rc and Rd can form a 5- or 6-membered heterocycloalkyl group together with the atom of nitrogen to which they are attached, wherein said heterocycloalkyl group may contain one or more additional heteroatoms selected from N, S or O; z is 0, 1 or 2; q is 0, 1, 2, 3 or 4; and its pharmaceutically acceptable salts, with the proviso that the compound of formula (1) is not N- [3- (cyclopentylsulfonyl) phenyl] -3- (3-pyridinyl) -2-propenamide; N- [4-ethoxy-3- (4-morpholinyl sulfonyl) phenyl] -3- (3-pyridinyl) -2-propenamide; N- [2- (1-Methylethoxy) -5- (4-morpholinyl sulfonyl) phenyl] -3- (3-pyridinyl) -2-propenamide; N- [2-ethoxy-5- (4-morpholinyl sulfonyl) phenyl] -3- (3-pyridinyl) -2-propenamide; N- [5 - [(hexahydro-1Hazepin-1-yl) sulfonyl] -2- (2,2,2-trifluorethoxy) phenyl] -3- (3-pyridinyl) -2-propenamide; N- [5 - [(diethylamino) sulfonyl] -2- (4-morpholinyl) phenyl] -3- (3-pyridinyl) -2-propenamide; N- [3 - [[(3-chlorophenyl) amino] sulfonyl] -4-methylphenyl] -3- (3-pyridinyl) -2-propenamide; N- [3 - [[(4-chlorophenyl) amino] sulfonyl] -4-methylphenyl] -3- (3-pyridinyl) -2-propenamide; 3- (3-pyridinyl) -N- [4 - [[(tetrahydro-1,1-dioxide-3-thienyl) amino] sulfonyl] phenyl] -2-propenamide; 3- (3-pyridinyl) -N- [3 - [[[3- (trifluoromethyl) phenyl] amino] sulfonyl] phenyl] -2-propenamide; and @@@ 3- (3-pyridinyl) -N- [1,4,5,6-tetrahydro-5 - [(4-methylphenyl) sulfonyl] pyrrolo [3,4-c] pyrazol-3-yl] - 2-propenamide

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